Targeting this protein may prevent COPD inflammation

A new study with mice paves the way to what could be the first treatment that actually prevents the progression of COPD, a lung disease that kills about 3 million people a year.

by U. MelbourneMay 8, 20183 minutes

Blocking a protein that stimulates the production of white blood cells could prevent the destructive inflammation of chronic obstructive pulmonary disease, a lung disease which kills about 3 million people a year, a study with mice shows.

Chronic inflammation slowly eats away at the lung tissue of people with emphysema or COPD, and the major culprits are specialized white blood cells called neutrophils and macrophages. While adept at fighting lung infections, the cells can also attack the lungs’ elastic fibers, leaving people struggling for breath and prone to chest infections.

There is no cure, and while abnormally high levels of white blood cells have long been associated with emphysema, scientists haven’t been sure about an underlying cause that drugs could effectively target.

Protein target

Now, the findings of a new study, which appears in the Journal of Clinical Investigation, opens the way for what could be the first treatment that actually prevents the disease from progressing, and provides a new biomarker to screen people for much earlier diagnosis.

“We found elevated levels of G-CSF in mice with COPD, and when it was eliminated, the excessive numbers of white blood cells in their lungs were markedly reduced and the lungs themselves no longer became diseased,” says senior author Margaret Hibbs, an immunologist associate professor at Monash University.

“Nothing previously has proved to be effective in treating patients with COPD, which is why this finding is so exciting. We can now attempt to target this protein.”

The genesis of the research goes back to a major international study, published in 2012, that highlighted a strong association between COPD and elevated numbers of white blood cells.

When they looked at the results, Hibbs and Gary Anderson, director of the Lung Health Research Centre at the University of Melbourne, were intrigued.

When follow up studies showed that high white blood cell counts were also associated with the damage COPD does to other tissues, like the heart, muscles, and bones, they decided to investigate.

“That really cemented in our minds that the white blood cells were a fundamental clue to follow,” Anderson says.

What about people?

The researchers then evaluated the effects of blocking G-CSF using mice genetically modified to be prone to COPD symptoms.

“When we blocked G-CSF, the effect was absolutely striking,” Anderson says. “It prevented not only the emphysema, but also the wider medical problems, whether it be the heart, muscles, or bone. We realized we had uncovered a potential pathway for treatments.”

COPD kills about 3 million people each year, making it the third most common cause of death worldwide behind heart disease and stroke. Globally there were an estimated 251 million cases of COPD in 2016.

Narrowing down an apparent cause of COPD in mice to G-CSF, however, doesn’t mean it works the same way in humans. Before they could contemplate moving into clinical trials, the team needed to know if the elevated levels of G-CSF in mice with COPD was replicated in patients suffering from COPD.

To investigate, they presented their findings to Lou Irving, a clinical respiratory researcher and director of clinical training at the Royal Melbourne Hospital, who gave access to a group of respiratory patients, with and without COPD, who volunteered to be sampled as a normal part of their care.

As the team suspected, they found that COPD in humans was correlated with high levels of G-CSF.

“We now have a very good case that we have indeed found a mechanism not just for preventing emphysema and chronic bronchitis in the lungs, but also for preventing the damaging medical conditions associated with it,” Anderson says.

“There are several safe ways to reduce G-CSF in people and this concept can now be tested in human clinical trials.”

Already established antibodies can block G-CSF. By simply adjusting the dose of any eventual therapeutic, clinicians could maintain the infection-fighting ability of these white blood cells while preventing the collateral damage that leads to COPD.

“We aren’t proposing to eliminate G-CSF but to keep it at levels within the normal range. That way we can preserve the normal defense function of these white blood cells but stop them from becoming over-aggressive to lung tissue and other body tissues.”

“This would be the first ever strategy that would not only treat the lung disease but the co-associated medical conditions at the same time. If successful, this has the potential to benefit the millions of people who suffer this terrible disease.”